N-(7-(1H-Imidazol-1-yl)-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl)benzamide, a New Kainate Receptor Selective Antagonist and Analgesic: Synthesis, X-ray Crystallography, Structure–Affinity Relationships, and in Vitro and in Vivo Pharmacology
| Autor: | Tommy N. Johansen, Birgitte Nielsen, Diletta Pasini, Darryl S. Pickering, Jakob S. Pallesen, Piero Temperini, Karla Frydenvang, Ana V. Paternain, Jette S. Kastrup, Stine Møllerud, Esmira Mamedova, Jesper T. Andreasen, Paulina Chalupnik, Juan Lerma, Rie Bager Hansen, Jan Bornholt, Marta Diaz-delCastillo |
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| Přispěvatelé: | Lundbeck Foundation, European Commission |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Physiology
Stereochemistry Cognitive Neuroscience Pain Kainate receptor AMPA receptor Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Homomeric Receptor Benzamide 030304 developmental biology 0303 health sciences Chemistry Glutamate receptor Cell Biology General Medicine Tail-flick 3. Good health X-ray diffraction Electrophysiology Ionotropic glutamate receptor NBQX Analgesia 030217 neurology & neurosurgery Tail flick test |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| Popis: | Selective pharmacological tool compounds are invaluable for understanding the functions of the various ionotropic glutamate receptor subtypes. For the kainate receptors, these compounds are few. Here we have synthesized nine novel quinoxaline-2,3-diones with substitutions in the 7-position to investigate the structure–activity relationship at kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Compound 11 exhibited the highest binding affinity across GluK1–3 while having selectivity toward kainate vs AMPA receptors. Compound 11 potently inhibited glutamate evoked currents at homomeric GluK1 and GluK3 receptors in HEK293 cells with Kb values of 65 and 39 nM, respectively. The binding mode of 11 in the ligand binding domain of GluK1 was investigated by X-ray crystallography, revealing that 11 stabilizes the receptor in an open conformation, consistent with its demonstrated antagonism. Furthermore, 11 was tested for analgesic effects in the mouse tail flick test where it significantly increased tail flick latency at doses where 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]-quinoxaline-7-sulfonamide (NBQX) was ineffective. This research was generously supported by the Lundbeck Foundation (S.M., D.S.P., K.F., and J.S.K.), GluTarget (J.B., T.N.J.), Danscatt (S.M., K.F., J.S.K.), and European Union Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie Grant Agreement No. 642720 (M.D.C). |
| Databáze: | OpenAIRE |
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